Even with the remarkable advances seen with cancer screening programs and increased public awareness of lifestyle risk factors, such as smoking and diet, and the landmark progress in oncology-based therapeutics we are still facing a net increase in the impact of cancer on the aging population for the foreseeable future. Therefore it remains of critical importance to maintain research focus on new therapeutic strategies as a composite of the overall approaches aimed at reducing the incidence and prevalence of cancer in the global population. In this regard the ability to produce effective vaccines that allow immune system recognition of cancer carbohydrate antigens continues to be a difficult to achieve and long term focus for cancer therapy. This R21 project is designed to answer just the first question in a very long and complex series of questions that may lead toward this important goal. Specifically, this R21 proposal exploits the recent discovery by the PI that complement protein C3 can be site-specifically chemically modified to generate C3-cancer carbohydrate bioconjugates that can also incorporate B-cell and/or T-cell epitopes. Given the known ability of C3-fragments to activate both B-cell and T-cell dependent immunity in vivo, it is plausible that if fully realized C3-cancer carbohydrate bioconjugates (such as the ones being designed and synthesized in this proposal), may offer the potential of being core components of new cancer immunotherapies directed against cancer-related carbohydrate antigens. It should be stressed that the full realization of this goal will require integrated research exploiting expertise in tumor immunology, complementology, autoimmunity and fundamental immunology which is way beyond the remit of this preliminary proposal, However, this preliminary R21 project is designed to generate the critical preliminary data from murine immunization with chemically-synthesized C3-cancer carbohydrate antigens that will hopefully support the hypothesis that such C3-bioconjugates can trigger anti-cancer carbohydrate B- and T-cell immune responses in mice, and as such warrant more integrated and in-depth proposals. PUBLIC HEALTH RELEVANCE: The ability to produce effective vaccines that allow immune system recognition of cancer carbohydrate antigens continues to be a difficult to achieve and long term focus for cancer therapy. This project is designed to answer just the first question in a very long series of questions toward this important goal Specifically, this R21 proposal exploits the recent discovery by the PI that complement protein C3 can be site-specifically modified with peptides and small molecules to generate C3-cancer carbohydrate bioconjugates. Given the known ability of C3-fragments to activate both B-cell and T-cell dependent immunity, it is plausible that if fully realized (requiring much more research beyond the remit of this preliminary proposal), C3-cancer carbohydrate bioconjugates (such as the ones being designed and synthesized in this proposal), could offer the potential of being core components of new cancer immunotherapies.